Generation of Cytotoxic T Cells and Dysfunctional CD8 T Cells in Severe COVID-19 Patients

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Gozzi-Silva, Sarah Cristina ; Oliveira, Luana de Mendonca ; Alberca, Ricardo Wesley ; Pereira, Natalli Zanete ; Yoshikawa, Fabio Seiti ; Pietrobon, Anna Julia ; Yendo, Tatiana Mina ; de Souza Andrade, Milena Mary ; Leuzzi Ramos, Yasmim Alefe ; Brito, Cyro Alves ; Oliveira, Emily Araujo ; Beserra, Danielle Rosa ; Orfali, Raquel Leao ; Aoki, Valeria ; da Silva Duarte, Alberto Jose ; Sato, Maria Notomi

• Document type: Journal article
• Source: CELLS; v. 11, n. 21, p. 18-pg., 2022-11-01.

Abstract

COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The viral infection can evolve asymptomatically or can generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia based on the severity of symptoms in patients affected with COVID-19 is frequent. However, the profiles of CD4+ and CD8+ T cells regarding cytotoxicity and antiviral factor expression have not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study was to evaluate the phenotypic and functional profile of T lymphocytes in patients with moderate and severe/critical COVID-19. During the pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe/critical cases). Notwithstanding lymphopenia, we observed an increase in the expression of CD28, a co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T lymphocytes as well as an increase in the frequency of CD4+ T cells, CD8+ T cells, and NK cells that express the immunological checkpoint protein PD-1 in patients with a severe/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T cells was already observed at the baseline level and scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T lymphocytes decreased the cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed by t-SNE, there were CD4+ T-cytotoxic and CD8+ T with low granzyme production, evidencing their dysfunction in severe/critical conditions. In addition, purified CD8+ T lymphocytes from patients with severe COVID-19 showed increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and, curiously, had reduced expression of TNF-alpha. The cytotoxic profile of CD4+ T cells may compensate for the dysfunction/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T cells and CD8+ T cells in the severity of acute COVID-19 infection. (AU)

• FAPESP's process: 19/25119-7 - Maternal-fetal interface: immunopathogenesis and vaccinal intervention in viral infections
• Grantee: Maria Notomi Sato
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/22448-0 - Analysis of natural killer memory cells and the antiviral response of CD8 + T cells in SARS-CoV-2 infection
• Grantee: Sarah Cristina Gozzi e Silva
• Support Opportunities: Scholarships in Brazil - Master